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Designer Proteins Hit the Runway

Sarah C.P. Williams

Self-assembling cages of proteins have been designed by two research teams, paving the way for future work on creating novel protein-based materials.

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Using two distinct methods, research teams have created self-assembling protein cages for the first time. The symmetrical cages can be used to contain other molecules, carry them to specific cellular targets, or form larger structured materials. These techniques provide several advantages over relying on existing proteins for tasks such as drug delivery.

The crystal structure of this tetrahedral protein cage confirms its organization. The cage was designed by scientist to self-assemble into this particular shape, an advance in protein design and assembly. Source: Todd Yeates

“There’s been a fair amount of work using viruses for trying to do these types of things, but generally viruses aren’t very amenable to further engineering,” said Todd Yeates of the University of California, Los Angeles, an author on the two new papers describing the methods. “The idea with these is that you can make a whole variety of cages and you have much more control over their size and shape.”

For a protein to self-assemble into a complex shape, Yeates and colleagues concluded, it must have two different interfaces that can bind to other similar proteins. Their method to achieve these double interfaces: attach two protein domains by a linker. Their first try at applying this didn’t work out; the geometry was off. But in their latest attempt, which is reported in the May 31 issue of Science (1), the proteins self-assemble into a hollow tetrahedron.

“Things are really starting to turn the corner now with being able to design assemblies more easily, but there’s still a fair amount of trial and error,” said Yeates.

In a separate paper published in the same issue of Science (2), a team of University of Washington researchers led by David Baker and Neil King—a former student of Yeates’—reported a different approach to the design process. Rather than attaching two protein domains to create two binding interfaces, they relied on only one existing protein. Then, they used a computer program to add a second binding interface to the protein. Like the UCLA team, they created a tetrahedral cage, as verified by electron micrograph and crystallography.

“I think both of these strategies can be successful going forward,” said Yeates. “The approach using a computer program is more easily generalizable and ultimately should be more powerful, but at the current time the programs that predict assemblies still have a fairly low success rate.”

Until the computer programs predicting assembly become more reliable, both methods work equally well, he said, and provide a starting point to create more complex protein designs.

“What we’d eventually like to do is try to make different kinds of protein architectures, including proteins whose assembly is triggered by a change in conditions or the addition of other molecules,” he said. This could lead to the development of materials responsive to their environment.

A second goal is to improve the techniques enough that results are easily reproducible, predictable, and have high success rates. “Ideally, we can improve the success rate for these strategies so that they can be applied in more typical lab settings instead of just a few specialized labs,” said Yeates.


  1. Lai Y-T., C. Duilio, and T.O. Yeates. 2012. Structure of a 16-nm cage designed by using protein oligomers. Science 336:1129.
  2. King N.P., W. Sheffler, M.R. Sawaya, B.S. Vollmar, J.P. Sumida, I. Andre, T. Gonen, T.O. Yeates, and D. Baker. 2012. Computational design of self-assembling protein nanomaterials with atomic level accuracy. Science 336:1171-1174.

Keywords:  protein design